An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy

Cedric Darini, Nour Ghaddar, Catherine Chabot, Gloria Assaker, Siham Sabri, Shuo Wang, Jothilatha Krishnamoorthy, Marguerite Buchanan, Adriana Aguilar-Mahecha, Bassam Abdulkarim, Jean Deschenes, Jose Torres, Josie Ursini-Siegel, Mark Basik and Antonis E. Koromilas ()
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Cedric Darini: Sir Mortimer B. Davis-Jewish General Hospital
Nour Ghaddar: Sir Mortimer B. Davis-Jewish General Hospital
Catherine Chabot: Sir Mortimer B. Davis-Jewish General Hospital
Gloria Assaker: McGill University
Siham Sabri: McGill University
Shuo Wang: Sir Mortimer B. Davis-Jewish General Hospital
Jothilatha Krishnamoorthy: Sir Mortimer B. Davis-Jewish General Hospital
Marguerite Buchanan: Sir Mortimer B. Davis-Jewish General Hospital
Adriana Aguilar-Mahecha: Sir Mortimer B. Davis-Jewish General Hospital
Bassam Abdulkarim: Research Institute of McGill University Health Centre
Jean Deschenes: University of Alberta
Jose Torres: McGill University
Josie Ursini-Siegel: Sir Mortimer B. Davis-Jewish General Hospital
Mark Basik: Sir Mortimer B. Davis-Jewish General Hospital
Antonis E. Koromilas: Sir Mortimer B. Davis-Jewish General Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21CIP1 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.

Date: 2019
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DOI: 10.1038/s41467-019-10138-8

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